Prescriber Update

Vol. 38 No. 2 June 2017

www.medsafe.govt.nz ISSN 1172-5648 (print) ISSN 1179-075X (online)

Contents

Quetiapine — Delivering Hepatic Reactions? 18 Adverse Reaction Reporting in Older Patients 18 Spotlight on Levetiracetam 19 DRESS: A Pleat for Help 20 Prescribing Cannabis-based Products 21 Fluoride Content in Toothpaste for Children 23 MARC’s Remarks: March 2017 Meeting 24 Dopamine Agonists and Impulse Control Disorders 25 Gathering Knowledge from Adverse Reaction Reports: June 2017 26 The Medsafe Files – Episode Four: New Medicines Assessment (Part 1) 27 Recent Approvals of Medicines Containing a New Active Ingredient 28 Mitochondrial Disorders: Medicines to Avoid 29 Quarterly Summary of Recent Safety Communications 31 MEDICINES MONITORING: Viekira Pak, Viekira Pak-RBV and Blood Glucose Control 31 Subscribe to Printed Editions of Prescriber Update 32 Quetiapine — Delivering Hepatic Reactions? occur. Hepatitis has been reported rarely and Key Messages hepatic failure very rarely during post-market monitoring. The exact mechanism of these zz Hepatic adverse effects may occur with hepatic reactions is currently unknown. the use of quetiapine. Therefore, precautions are recommended when zz The most commonly reported hepatic using quetiapine: adverse reaction is elevated liver enzymes. ŸŸ in patients with pre-existing hepatic disorders zz Cases of hepatitis and hepatic failure ŸŸ in patients who are also being treated with have been reported. potentially hepatotoxic medicines zz Caution is advised in patients with ŸŸ if signs or symptoms of hepatic impairment known hepatic impairment, in patients develop during treatment. who are being treated with potentially Dose adjustments or a reduced starting dose hepatotoxic medicines or if there are of quetiapine may be needed. Data sheets for treatment-emergent signs or symptoms quetiapine products are in the process of being of hepatic impairment. updated with this information.

Healthcare professionals are reminded of The Centre for Adverse Reactions Monitoring the potential risk of hepatic adverse effects (CARM) has received 13 reports of hepatobiliary associated with the use of quetiapine, an atypical reactions with the use of quetiapine. The majority antipsychotic. of these reports concerned increases in hepatic enzymes (also referred to as ‘hepatic function Quetiapine is extensively metabolised by the abnormal’ in the CARM database). There has also liver. Elevations in liver enzyme levels, including been one case of a hepatic cyst and one case of aspartate aminotransferase(AST), alanine hepatic failure reported to CARM. aminotransferase (ALT) and gamma-GT may

Adverse Reaction Reporting in Older Patients Reporting suspected adverse reactions to the in the last five years in both the 65–79 year age Centre for Adverse Reactions Monitoring (CARM) group (6.2% of the 3,729 cases) and the 80 years is important for all patients independent of age. and over group (13.4% of the 1,265 cases) (Table 1). It is particularly important for older patients who are more likely to be affected by adverse reactions Number of cases 5,000 to medicines due to co-morbidities and reduced 338 renal and hepatic function. Reporting these 827 4,000 264 239 232 192 suspected adverse reactions allows Medsafe 756 719 765 662 and CARM to identify possible safety concerns 3,000 specific to older people. 2,000 During the five-year period from 2012 to 2016, 3233 3134 3914 3255 3090 17.3% of all cases reported to CARM were in 1,000 the 65–79 year age group and 5.8% of all cases were in the 80 years and over age group. These 0 2012 2013 2014 2015 2016 proportions have remained consistent over the Less than 65 years 65–79 years last five years (Figure 1). Please note that one 80 years and over report may contain multiple medicines and multiple reactions. Figure 1: Number of cases of suspected adverse reactions to medicines reported to CARM from Dabigatran was most commonly associated with 2012 to 2016 a suspected adverse reaction reported to CARM

18 Prescriber Update 2017; 38(2) June Interestingly, no bleeding reactions were in the For the five-year period, the most commonly top five reactions reported. This is likely due to reported suspected reaction to a medicine taken there being multiple bleeding terms available. by patients in both age groups was rash (Table 2). In the 65–79 year age group, rash was reported in Table 1: Top five medicines reported to CARM in 5.5% of the 3,729 cases. In the 80 years and over older patients in the last five years, 2012–2016 age group, rash was reported in 5.4% of the 1,265 cases. Age 65–79 Age 80 and over Table 2: Top five reactions reported to CARM in 1 Dabigatran Dabigatran older patients in the last five years, 2012–2016 2 Iohexol Zoledronic acid Age 65–79 Age 80 and over 3 Influenza vaccine Influenza vaccine 1 Rash Rash 4 Zoledronic acid Clozapine 2 Nausea Dyspnoea 5 Clozapine Omeprazole 3 Urticaria Pruritus The contrast agent, iohexol, was the second most 4 Dyspnoea Nausea reported medicine associated with a suspected adverse reaction in the 65–79 year age group 5 Injection site inflammation Rash pruritic (4.9% of cases). In the 80 years and over age group, the second most reported medicine was Healthcare professionals are encouraged to zoledronic acid (5.3% of cases). The influenza report any suspected adverse reaction(s) to CARM vaccine was the third most reported medicine in (https://nzphvc.otago.ac.nz/). Information both age groups (4.9% of cases in the 65–79 year about how to submit an adverse reaction report age group and 3.6% of cases in the 80 years and can be found on the Medsafe website (www. over group). medsafe.govt.nz/profs/adverse.asp) or on the Clozapine is included in the top five medicines CARM website (https://nzphvc.otago.ac.nz/ reported in both age groups. This is likely due reporting/). to the monitoring requirements associated with clozapine.

Spotlight on Levetiracetam The Prescriber Update survey ran between Key Messages 3 March 2016 and 8 April 2016. Feedback from this survey indicated that readers would like zz Levetiracetam is an antiepileptic to see more reviews about the safety of specific medicine used as add-on therapy in the medicines and classes of medicines. The first treatment of epilepsy. spotlight article is on levetiracetam. zz The major safety concern with use of Levetiracetam is approved as add-on treatment levetiracetam is an increase in mood for partial onset seizures with or without disorders including suicidality. secondary generalisation in patients aged six zz Patients, their relatives and friends years and older 1,2. should be asked to closely monitor Levetiracetam is an unusual medicine in that for changes in behaviour and to seek almost 100% of the dose is absorbed via the oral immediate medical attention should any route. For this reason, it is generally considered changes occur. acceptable to change brands without the zz Monitoring renal function and changes need for additional monitoring3. However, in dose may be required in patients with reactions associated with changing the brand of impaired renal function. levetiracetam have been reported to the Centre for Adverse Reactions Monitoring (CARM).

Prescriber Update 2017; 38(2) June 19 Levetiracetam is excreted renally with around mood disorder, depression, hyponatraemia, 95% of the dose excreted in the urine. A dose neutropenia, suicidal ideation, vomiting, adjustment based on the patient’s creatinine aggressive reaction and brand switch. All of clearance is necessary in patients with moderate these potential adverse reactions, excluding to severe renal impairment1. brand switch, are listed in the New Zealand data sheet for levetiracetam1,7. The only contraindication for use is hypersensitivity reactions. Levetiracetam must Please continue to report any adverse reactions not be used in patients allergic to levetiracetam, for levetiracetam and any other medicine to other pyrrolidone derivatives or any of the CARM. Reports can be submitted on paper or excipients in the medicine. The excipients are electronically (https://nzphvc.otago.ac.nz/). listed in the data sheet, Consumer Medicine References Information (www.medsafe.govt.nz/ 1. REX Medical Limited. 2014. Everet Data Sheet 22 December Medicines/infoSearch.asp) and in the product 2014. URL: www.medsafe.govt.nz/profs/Datasheet/e/ application search on the Medsafe website everettab.pdf (accessed 20 April 2017). (www.medsafe.govt.nz/regulatory/DbSearch. 2. New Zealand Formulary. 2017. Levetiracetam. NZF v58 asp). 1 April 2017. URL: www.nzf.org.nz/nzf_2641 (accessed 20 April 2017). All patients who are taking levetiracetam should 3. Medicines and Healthcare products Regulatory Agency. be closely monitored for changes in behaviour. 2013. Antiepileptic drugs: new advice on switching Psychiatric disorders that have been associated between different manufacturers’ products for a particular drug. Drug Safety Update 14 November 2013. URL: www. with the use of levetiracetam include aggression, gov.uk/drug-safety-update/antiepileptic-drugs-new- abnormal behaviour, suicide and suicidality1. advice-on-switching-between-different-manufacturers- Patients, relatives and friends should be products-for-a-particular-drug (accessed 20 April 2017). encouraged to monitor behaviour and to seek 4. Medsafe. 2016. Antiepileptic Medicines and Suicide. Prescriber Update 37(1): 6–7. URL: immediate medical advice if changes are noticed. www.medsafe.govt.nz/profs/PUArticles/March2016/ Healthcare professionals are reminded to inform AntilepilepticMedicinesAndSuicide.htm (accessed 20 patients and their families and caregivers of the April 2017). potential risk of suicidality1. 5. Medsafe. 2009. Antiepileptic medicines – increased risk of suicidality. Prescriber Update 30(2): 11. URL: www. Further information regarding antiepileptic medsafe.govt.nz/profs/PUArticles/Antiepileptics%20 medicines and suicide can be found in previous &%20suicidality-May09.htm (accessed 20 April 2017). 6. Medsafe. 2010. Suicidality – a rare adverse effect. Prescriber Update articles 4-6. Prescriber Update 31(1): 7. URL: www.medsafe.govt.nz/ At 31 December 2016, the Centre for Adverse profs/PUArticles/Suicidality%20-%20a%20rare%20 adverse%20effect.htm (accessed 20 April 2017). Reactions Monitoring (CARM) had received 35 7. Pharmabroker Sales Ltd. 2016. Keppra data sheet 6 May reports in which levetiracetam was reported as 2016. URL: www.medsafe.govt.nz/profs/Datasheet/k/ a suspect medicine. Reaction terms that were Keppratab.pdf (accessed 26 April 2017). reported twice or more include irritability,

DRESS: A Pleat for Help Drug reaction with eosinophilia and systemic Key Messages symptoms (DRESS) is a potentially life- threatening drug-induced hypersensitivity zz DRESS is characterised by rash, reaction with an estimated mortality of 10%1. fever, haematologic abnormalities, It is characterised by rash, fever, haematologic lymphadenopathy and internal organ abnormalities (eosinophilia, atypical involvement. lymphocytosis), lymphadenopathy and internal zz Medicines most commonly associated organ involvement (liver, kidneys, lungs)1–3. with DRESS are antiepileptics and Healthcare professionals are reminded there allopurinol. are many medicines that have been associated zz Olanzapine has recently been associated with DRESS (Table 1). Antiepileptics (eg, with DRESS. carbamazepine, lamotrigine, phenytoin) and allopurinol are the medicines most frequently associated with DRESS in the scientific

20 Prescriber Update 2017; 38(2) June Table 1: Examples of medicines associated with DRESS5

Frequently reported Allopurinol, carbamazepine, lamotrigine, phenytoin, sulfasalazine, vancomycin, minocycline, dapsone, sulfamethoxazole

Also reported Beta-lactam antibiotics, nevirapine, olanzapine, oxcarbazepine, strontium ranelate, telaprevir

4 literature . Sulphonamides, minocycline and References 5 vancomycin may also cause DRESS . 1. Husain Z, Reddy BY, Schwartz RA. 2013. DRESS syndrome: Part I. Clinical perspectives. Journal of the American Most recently, in May 2016, the United States Academy of Dermatology 68: 693 e1–14; quiz 706–8. Food and Drug Administration (FDA) warned 2. Bocquet H, Bagot M, Roujeau JC. 1996. Drug-induced that olanzapine may cause DRESS6. Medsafe is pseudolymphoma and drug hypersensitivity syndrome working to ensure that the New Zealand data (Drug Rash with Eosinophilia and Systemic Symptoms: sheets for all olanzapine-containing products DRESS). Seminars in Cutaneous Medicine and Surgery 15: 250 –7. include information on DRESS. 3. Husain Z, Reddy BY, Schwartz RA. 2013. DRESS syndrome: The Centre for Adverse Reactions Monitoring Part II. Management and therapeutics. Journal of the American Academy of Dermatology 68: 709 e1–9; quiz 18–20. (CARM) has received 39 case reports that included 4. Kardaun SH, Sekula P, Valeyrie-Allanore L, et al. 2013. a diagnosis of DRESS from 1 January 2012 to 31 Drug reaction with eosinophilia and systemic symptoms December 2016. The most commonly reported (DRESS): an original multisystem adverse drug reaction. suspected medicines were allopurinol (13 cases), Results from the prospective RegiSCAR study. British Journal of Dermatology 169: 1071–80. vancomycin (4), piperacillin/tazobactam and 5. Roujeau JC. 2017. Drug reaction with eosinophilia and sulfasalazine (3 each). systemic symptoms (DRESS). Waltham, MA: UpToDate. Further information on DRESS is available URL: www.uptodate.com/contents/drug-reaction-with- eosinophilia-and-systemic-symptoms-dress (accessed in a previous edition of Prescriber Update 20 April 2017). (www.medsafe.govt.nz/profs/PUArticles/ 6. US FDA. 2016. FDA warns about rare but serious skin DRESSsyndromeJune2011.htm). reactions with mental health drug olanzapine. Drug Safety Communication 10 May 2016. URL: www.fda. gov/downloads/Drugs/DrugSafety/UCM499603.pdf (accessed 20 April 2017).

Prescribing Cannabis-based Products The use of cannabis-based products for medicinal manufacturing practice (GMP) standards for purposes is attracting considerable public pharmaceutical-grade products. Evidence interest in New Zealand and internationally. In of the composition of these products, the New Zealand, over the past few years, there has reproducibility of the composition from batch been increasing public pressure on prescribers, to batch and the stability of the products in use is the Ministry of Health and Government to not available. Evidence of the safety and efficacy enable greater access to products derived from of most of the individual products from clinical the cannabis plant. Cannabinoid products can trials is lacking. Nonetheless, an evidence base also be manufactured synthetically and have for the use of cannabis for medicinal purposes been available in the United States and some is developing. other countries for several years. However, most advocates of the medical benefits of cannabis Evidence believe that products derived from plant material There are now a large number of clinical trials are more effective. of cannabis-based medicines reported and 1–3 The Government prefers to refer to ‘cannabis- several systematic reviews . The majority based products’ rather than ‘medicinal cannabis’ of trials have used synthetically produced because the majority of the products available medicines. Evidence of the efficacy of cannabis- do not meet the criteria normally associated based medicines in certain conditions is now with a medicine. That is, the products are emerging and there is good agreement across the not manufactured to international good systematic reviews as to the benefits of cannabis- based products and also the potential harms.

Prescriber Update 2017; 38(2) June 21 The most recent and comprehensive review is The Code of Health and Disability Services Consumers’ Health Effects of Cannabis and Cannabinoids: The Rights to ensure that the patient is fully informed Current State of Evidence and Recommendations and that written consent is obtained. Please see for Research1. the Medsafe Guidelines for Use of Unapproved Medicines (www.medsafe.govt.nz/profs/RIss/ Information for Healthcare Professionals unapp.asp). Health Canada has a comprehensive publication Other products that the Ministry of Health Information for Health Care Professionals: believes are of pharmaceutical grade or are GMP Cannabis (marihuana, marijuana) and the certified for at least part of the manufacturing cannabinoids (www.hc-sc.gc.ca/dhp-mps/ process are Tilray and Bedrocan. marihuana/med/infoprof-eng.php). It was published in February 2013 and an update is due Tilray products are manufactured by a Canadian later in 2017. company. Tilray has oil and capsule products that have been produced to GMP standards This publication provides comprehensive for the cultivation and extraction of the active information on pharmacology and potential ingredients, but the Ministry of Health does not therapeutic uses. Please note that in Canada, consider that the products are pharmaceutical cannabis is available for smoking from federally grade. licensed producers and since the publication of this document patients have again been allowed Bedrocan products are obtained from certified to grow their own cannabis pursuant to a medical sites in the Netherlands. Bedrocan has a range of document. standardised plant (cannabis flowers, often called flos, and granulated plant material) products The Therapeutic Goods Administration (TGA) with different standardised concentrations of in Australia is undertaking a systematic review THC and CBD. The recommended method of with the aim to develop clinical guidelines to administration for Bedrocan is via a medical educate and assist prescribing choices. They vaporisation device. aim to complete this review in 2017. In the interim, the Queensland Department of Health Other cannabinoid-based medications has developed the first clinical guidelines for include Marinol containing dronabinol (a Australia (www.health.qld.gov.au/__data/ synthetic THC), Cesamet containing nabilone assets/pdf_file/0023/634163/med-cannabis- (a synthetic analogue of THC) and Syndros, a clinical-guide.pdf). liquid formulation of dronabinol. These are medicines based on cannabinoids but have The Queensland Department of Health notes been manufactured synthetically rather than that this guide will be replaced by the national derived from cannabis plant material. They are document when completed. The information is all pharmaceutical grade, FDA approved and can mostly transferable to the New Zealand situation. legally be exported from the United States. One principal difference is that Sativex is available in New Zealand, whereas it is imported on an All other available cannabis-based products individual patient approval basis in Australia. produced in the United States that the Ministry of Health is aware of are not pharmaceutical Products grade. Cannabis-based products derived from At the time of writing, Sativex is the only cannabis- plant material are also classified as Schedule 1 based medicine with consent (approval) for substances, which means that they cannot be distribution in New Zealand. Sativex is indicated legally exported from the United States. as add-on treatment for symptom improvement To date, the Ministry of Health has only in patients with moderate to severe spasticity received applications to prescribe and import due to multiple sclerosis who have not responded one particular Tilray product. The Ministry of adequately to other anti-spasticity medication Health has not tested the availability of the other and who demonstrate clinically significant products listed above. improvement in spasticity-related symptoms during an initial trial of therapy. Sativex for other Application Process indications is unapproved. Cannabis-based products are Class B1 or C1 All other cannabis-based products are controlled drugs and Ministerial approval is unapproved in New Zealand. Prescribers need required before these can be prescribed, supplied to be clear on their responsibilities under the or administered, in accordance with Regulation 22 of the Misuse of Drugs Regulations 1977.

22 Prescriber Update 2017; 38(2) June Ministerial approval is now delegated to the Further information and application forms Ministry of Health for all types of cannabis-based can be found on the Ministry of Health website products. (www.health.govt.nz/our-work/regulation- health-and-disability-system/medicines- To prescribe cannabis-based products: control/prescribing-cannabis-based- 1. an application to the Ministry of Health is products). required in most cases. The exception is If you have any questions relating to an application, when prescribing Sativex for the consented or potential application, for a cannabis-based condition of multiple sclerosis. In this case, product please email medicinescontrol@moh. a general ministerial approval has been govt.nz gazetted to allow medical practitioners with a vocational scope of practice of Internal References Medicine (specialising in neurology), or a 1. The National Academy of Sciences, Engineering and general practitioner on the recommendation Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and of a neurologist, to prescribe Sativex for Recommendations for Research. Washington, DC: The multiple sclerosis without an application to National Academies Press. doi: 10.17226/24625 (accessed the Ministry. 20 April 2017). 2. Barnes MP, Barnes JC. 2016. Cannabis: The Evidence for 2. a specialist needs to be involved in the Medical Use. London: All-Party Parliamentary Group application process in all instances, and for Drug Policy Reform. URL: www.drugsandalcohol. needs to make the application to the ie/26086/ (accessed 20 April 2017). Ministry of Health, except for applications 3. Whiting PF, Wolff RF, Deshpande S, et al. 2015. Cannabinoids for Medical Use, A Systematic Review and Meta-analysis. for off-label uses of Sativex when a GP can JAMA 313(24): 2456–73. doi:10.1001/jama.2015.6358 apply following the recommendation of a (accessed 20 April 2017). specialist.

Fluoride Content in Toothpaste for Children Fluoride works topically primarily by reducing Key Messages demineralisation and enhancing remineralisation zz Reduction of dental caries by fluoride of enamel, reducing the susceptibility of the toothpaste is balanced against the teeth to caries progression. A sustained level of increased risk for dental fluorosis due to fluoride in plaque and on the enamel surface is toothpaste ingestion by young children. desirable and one important source is fluoride toothpaste. Fluoride in toothpaste is usually in zz Toothpastes containing less than 1,000 the form of sodium fluoride (NaF) or sodium ppm fluoride are not recommended for monofluorophosphate (MFP). use at any age in New Zealand. Commercially available fluoride toothpastes for zz To minimise the risk of ingestion of general sale in New Zealand have differing levels toothpaste, children should be supervised of fluoride content ranging from approximately when brushing their teeth, a smear of 500 parts per million (ppm) to 1,450 ppm toothpaste (five years and under) or a pea- fluoride. The 500 ppm formulations are labelled sized amount (six years and over) should for children under six years by manufacturers, be used and children should be taught to leading to confusion for consumers, as these low spit out any excess. fluoride toothpastes are not recommended at any zz Toothpaste should be kept out of reach of age in New Zealand1. children. The New Zealand Guidelines for the Use of Fluoride recommends that 1,000 ppm fluoride toothpaste The use of fluoride toothpaste is an important is used for children of all ages2. A recent Cochrane public health measure to both prevent and reduce review found limited evidence of any caries the severity of dental caries in all age groups. The preventive effect following use of toothpaste with protective effect of fluoride against caries is well less than 1,000 ppm fluoride3. Commencing tooth recognised. brushing with fluoride toothpaste before two

Prescriber Update 2017; 38(2) June 23 years of age is associated with enhanced caries children and the lack of evidence of moderate or prevention. severe dental fluorosis in New Zealand children8. The beneficial effects of fluoride toothpaste must Pharmacies and dental practices can also supply be counterbalanced against the risk of dental a 5,000 ppm fluoride toothpaste, which is not fluorosis from its ingestion. The risk of dental suitable for general use, but may be recommended fluorosis is of aesthetic concern and relates to in specific cases mainly in adults and in older ingestion of excess fluoride in children under age children with high levels of dental caries. This five years. toothpaste should be limited to use on the recommendation of an oral health professional. New Zealand studies show that the prevalence of diffuse enamel opacities that may be fluoride- References related has not increased over time and that 1. Li J, Dallas S, McBride-Henry K. 2016. Use of full strength all cases recorded were either mild or very fluoride toothpaste among preschoolers in New Zealand, 4–6 and factors determining choice. New Zealand Medical mild . The evidence regarding the role of Journal 129: 44–51. fluoride toothpaste in contributing to the risk 2. New Zealand Guidelines Group. 2009. Guidelines for the Use of fluorosis is conflicting and may be related to of Fluoride. Wellington: Ministry of Health. the amount used, the concentration used and 3. Walsh T, Worthington HV, Glenny AM, et al. 2010. Fluoride commencing use before age 12–14 months7. toothpastes of different concentrations for preventing dental caries in children and adolescents. The Cochrane Database New Zealand recommendations for toothpaste of Systematic Reviews. CD007868. doi: 10.1002/14651858. use in young children balance the issue of caries CD007868.pub2 (accessed 26 April 2017). prevention and avoidance of moderate or severe 4. Kanagaratnam S, Schluter P, Durward C, et al. 2009. Enamel defects in 9-year-old children living in fluoridated and dental fluorosis. The recommendation to use nonfluoridated areas of Auckland, New Zealand. Community toothpaste of at least 1,000 ppm fluoride addresses Dentistry and Oral Epidemiology 37: 250–9. the lack of evidence of a caries preventive effect 5. Schluter PJ, Kanagaratnam S, Durward C, et al. Prevalence for toothpaste below this concentration. of enamel defects and dental caries among 9-year-old Auckland children. New Zealand Dental Journal 2008; The recommendation to use a smear of toothpaste 104: 145-152. for children five years and under controls the 6. Mackay TD, Thomson WM. 2005. Enamel defects and dental amount of toothpaste that should be used. The caries among Southland children. New Zealand Dental Journal 101: 35–43. recommendation to commence use of toothpaste 7. Wright JT, Hanson N, Ristic H, et al. 2014. Fluoride as soon as teeth begin to emerge (approximately toothpaste efficacy and safety in children younger than 6 six months) recognises that teeth are at risk of years. Journal of the American Dental Association 145:182–9. dental caries from that time, the high levels of 8. Ministry of Health. 2010. Our Oral Health: Key findings early childhood dental caries in New Zealand of the 2009 New Zealand Oral Health Survey. Wellington: Ministry of Health.

MARC’s Remarks: March 2017 Meeting The Medicines Adverse Reactions Committee The MARC discussed Medsafe’s proposed (MARC) met on 9 March 2017 to discuss a number monitoring for the National Immunisation of medicine-related safety issues. Schedule change for varicella vaccine (Varilrix) against chickenpox and considered this to The MARC discussed the concomitant use of be adequate. Healthcare professionals are opioids, benzodiazepines and other CNS encouraged to report any suspected adverse depressants and the risk of serious side effects. reactions to varicella vaccines to the Centre for Usage trends, deaths, over-the-counter (OTC) Adverse Reactions Monitoring (CARM). availability of codeine and other opioids, the amount funded by PHARMAC on prescription, It is also important to note that Varilrix and prescribing practices in primary and secondary Varivax are varicella vaccines used to vaccinate care, and information included in data sheets against chickenpox and can be used in children, were discussed. Further information on the whereas Zostavax is a zoster vaccine used for the MARC’s discussion on this topic can be found on prevention of shingles in individuals 50 years the Medsafe website (www.medsafe.govt.nz/ of age and above. Further information on the profs/adverse/Minutes169.htm).

24 Prescriber Update 2017; 38(2) June differences between these vaccines can be found Drug Administration (www.fda.gov/Drugs/ in a previous edition of Prescriber Update1. DrugSafety/ucm532356.htm). The MARC discussed the use of anaesthetic The MARC noted the revised dosing and sedative agents in young children. Clinical recommendations for use of etoricoxib for studies conducted in humans are predominantly rheumatoid arthritis and ankylosing spondylitis. observational and have shown conflicting Healthcare professionals are reminded that the results for neurotoxicity and effects on brain recommended dose listed in the data sheet for development. It is not clear if the association is these indications is now 60 mg or 90 mg once a true effect of anaesthetic agents, the surgery daily. The minimum effective daily dose is 60 mg or underlying condition requiring surgical once daily and dose escalation to 90 mg should be intervention, or due to uncontrolled confounding considered on an individual patient basis. of other factors. Further information on this meeting can be found Overall, the MARC considered that the evidence on the Medsafe website (www.medsafe.govt.nz/ for an association between the use of anaesthetics profs/adverse/Minutes169.htm). in young children and risk of neurotoxicity was References equivocal, but that parents should be informed 1. Medsafe. 2015. Varicella Zoster Virus Vaccines — Medication about this safety concern. Further information Errors. Prescriber Update 36(3): 40. URL: www.medsafe. is available from the United States Food and govt.nz/profs/PUArticles/Sep2015/VaricellaVaccines. htm (accessed 20 April 2017).

Dopamine Agonists and Impulse Control Disorders disastrous personal and financial consequences. Key Messages Patients may be embarrassed about their behaviour and may not volunteer that they are zz Impulse control disorders are a recognised unable to control, for example, their spending or adverse effect associated with the use of gambling. dopaminergic medicines. The Centre for Adverse Reactions Monitoring zz Impulse control disorders include (CARM) has received two reports of compulsive compulsive shopping, problem gambling, gambling associated with the use of dopamine binge-eating and hypersexuality. agonists. zz Prescribers are reminded to enquire about 1. 2007: problem gambling reported in a symptoms of impulse control disorders 55-year-old female in association with when reviewing patients on dopamine ropinirole and paroxetine. Ropinirole was agonists or levodopa. stopped, but the outcome was unknown. Impulse control disorders are a recognised 2. 2008: problem gambling reported in adverse effect associated with the use of a 74-year-old male in association with dopaminergic medicines, including dopamine ropinirole, levodopa, clonazepam, selegiline receptor agonists and levodopa. Currently and doxazosin. The patient recovered approved dopamine receptor agonists include following withdrawal of ropinirole. ropinirole, pramipexole, bromocriptine, Prescribers are reminded to enquire about pergolide, apomorphine and cabergoline. symptoms of impulse control disorders when Levodopa is approved in combination products reviewing patients on dopamine agonists or containing either benserazide or carbidopa. levodopa. Reduction in the dose or tapered Impulse control disorders include compulsive discontinuation of the dopaminergic medicine shopping, problem gambling, binge-eating should be considered if symptoms of an impulse and hypersexuality. Patients and their family/ control disorder develop during treatment with caregiver should be alerted to the possibility these medicines. of these adverse reactions, which can have

Prescriber Update 2017; 38(2) June 25 Gathering Knowledge from Adverse Reaction Reports: June 2017 Adverse reaction reporting is an important component of medicine safety monitoring. Case reports can highlight significant safety issues concerning therapeutic products and their use. A selection of recent informative cases from the Centre for Adverse Reactions Monitoring (CARM) database is presented below.

CARM ID: 123194 The unintended pregnancy occurred approximately one year after Age: 29 Jadelle insertion and about six months after starting rifampicin. Gender: Female Medicine(s): Jadelle, Rifampicin The Jadelle data sheet (www.medsafe.govt.nz/profs/Datasheet/j/ Reaction(s): Unintended Jadelleimplant.pdf) states that rifampicin diminishes the efficacy of pregnancy Jadelle by enzyme induction. Enzyme induction can be observed within a few days of treatment and may be sustained for about four weeks after cessation of the inducer.

CARM ID: 123149 The patient experienced hyperammonaemia encephalopathy. On Age: 15 review, the patient was found to have an elevated sodium valproate Gender: Male level and five times normal range of ammonia in blood. Medicine(s): Sodium valproate Reaction(s): Hyperammonaemia The sodium valproate data sheet (www.medsafe.govt.nz/profs/ Datasheet/e/Epilimtabsyrliqiv.pdf) notes hyperammonaemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Patients who develop symptoms of unexplained hyperammonaemic encephalopathy while receiving valproate therapy should be evaluated for underlying urea cycle disorders.

CARM ID: 123120 Five days after starting venlafaxine the patient’s serum sodium had Age: 78 dropped to below 120 mmol/L. A week after discontinuing venlafaxine, Gender: Female the patient’s serum sodium levels had returned to baseline. Medicine(s): Venlafaxine The data sheet for venlafaxine (www.medsafe.govt.nz/profs/ Reaction(s): Hyponatraemia Datasheet/e/Efexorxrcap.pdf) states cases of hyponatraemia may occur with venlafaxine. Older patients, patients taking diuretics and patients who are otherwise volume depleted, may be at greater risk for this event. These have resolved on discontinuation of the drug.

CARM ID: 120887 The patient’s severe eczema was treated with topical and systemic Age: 12 steroids. The patient developed bilateral cataracts with vision reduced Gender: Male to light perception. Medicine(s): Prednisone, Methylprednisolone, The prednisone data sheet (www.medsafe.govt.nz/profs/ Hydrocortisone Datasheet/a/Apoprednisonetab.pdf) states that prolonged use Reaction(s): Bilateral cataracts of corticosteroids may produce subcapsular cataracts and nuclear cataracts (particularly in children).

26 Prescriber Update 2017; 38(2) June The Medsafe Files — Episode Four: New Medicines Assessment (Part 1) that the medicine will be used on a restricted Key Messages basis for the treatment of a limited number of zz Before medicines and related products patients. Provisional consent is only granted for can be sold in New Zealand, a New a period not exceeding two years and will then Medicine Application must be submitted expire, unless the sponsor applies for a renewal. to Medsafe to seek the Minister’s consent to distribute a medicine. Clinical Assessment Supporting data must be included in an zz Consent to distribute a medicine may be application to demonstrate the safety, efficacy attained via a full evaluation process or and quality of the ingredients and the final an abbreviated evaluation process. product. The regulatory assessment of new zz Provisional consent may be granted when medicines ideally follows pharmaceutical it is desirable for a medicine to be sold, product development. Medsafe evaluators carry supplied or used on a restricted basis out pharmaceutical chemistry and clinical for the treatment of a limited number of assessments. patients. If a pharmaceutical company wishes to sell or zz The Medicines Assessment Advisory distribute a medicine in New Zealand, data from Committee provides advice to the preclinical studies must be submitted as part of Minister of Health on the benefits and the application. Data includes: risks of new medicines. ŸŸ toxicity studies ŸŸ mutagenicity studies New Medicine Applications (NMAs) ŸŸ carcinogenicity studies Medicines and related products (see Section 2 of the Medicines Act 1981 [the Act] for definitions) ŸŸ single and repeated dose toxicity (in two need consent from the Minister of Health before species) being marketed in New Zealand. When seeking ŸŸ first in human studies consent to distribute a new medicine, a New ŸŸ dose-ranging studies Medicine Application (NMA) must be submitted to Medsafe by the New Zealand sponsor. A ŸŸ pivotal trials. new medicine is a medicine for which consent Parts 2 and 3 of Episode Four: New Medicines for distribution in New Zealand has not been Assessment will cover pharmaceutical chemistry granted or the approval has lapsed. assessment and pharmaceutical Good Medsafe also has an abbreviated evaluation Manufacturing Practice and will be included in procedure, which is based on a medicine’s upcoming editions of Prescriber Update. approval by another recognised regulatory agency (eg, European Medicines Agency, Medicines Assessment Advisory Committee Therapeutic Goods Administration of Australia, (MAAC) Health Canada). A review of overseas regulatory After the evaluation of a NMA, Medsafe reports does not mean that the originator evaluators will make a recommendation on approval will be adopted in full by Medsafe. whether or not consent should be granted. This evaluation process is not applicable to all In instances when Medsafe is not able to medicine applications. recommend that consent is granted, applications Applications can also be made for provisional can be referred to the Medicines Assessment consent (under Section 23 of the Act). Provisional Advisory Committee (MAAC). The MAAC has consent is defined mainly by the clinical need. expertise in the safety, quality and efficacy of It is ideally suited to medicines still undergoing medicines and provides advice to the Minister clinical development but where it is desirable of Health on the benefits and risks of new that patients have early access. It is anticipated medicines.

Prescriber Update 2017; 38(2) June 27 Applications are referred to the MAAC in CMNs are assessed to ensure the change does situations such as when: not adversely affect the quality or benefit/risk balance of the medicine. ŸŸ it is for a new vaccine indicated in children ŸŸ it is a novel technology such as medicines Some product changes such as additional derived from stem cells and nanotech indications, new sites of drug substance manufacture, failure to respond to requests ŸŸ it is for a medicine that has been withdrawn or for information or extensions to the current refused consent by a recognised regulator indication or dosing regimen require additional ŸŸ other regulators differ in their approvals assessment by Medsafe. These applications ŸŸ it is a world first new chemical entity may be referred to the Minister of Health under Section 24(5) of the Act when the proposed ŸŸ Medsafe is unsure whether to recommend changes are of such a character or degree that the consent. medicine should not be distributed without the consent of the Minister of Health. Consequently, Change Medicine Notifications (CMNs) CMNs referred under Section 24(5) typically have The sponsor of a product must notify the a longer processing time frame than a CMN. Director-General of Health of planned changes Further information on application processes and to an approved product. This type of application the MAAC is outlined in Part 2 of the Guideline is called a Change Medicine Notification (CMN) on the Regulation of Therapeutic Products in and includes data sheet updates and package New Zealand (GRTPNZ) (www.medsafe.govt.nz/ labelling updates for over-the-counter medicines. regulatory/Guideline/GRTPNZ/Part2.pdf).

Recent Approvals of Medicines Containing a New Active Ingredient

For period 16 January 2017 to 15 April 2017

Trade Name (active Dose form and strength Therapeutic area ingredient)*

Descovy (emtricitabine/ Tablet 200 mg/10 mg and HIV-1 infection tenofovir)† 200 mg/25 mg

Eliriduc/Golyra/Praluent Solution for injection 75 mg/ Hypercholesterolaemia (alirocumab)§ mL and 150 mg/mL

Ilevro (nepafenac) Eye drops, suspension 0.3% Postoperative pain and inflammation associated with cataract surgery

Perjeta (pertuzumab) Concentrate for infusion 420 HER2-positive breast cancer mg/14 mL

Tecentriq (atezolizumab)# Concentrate for infusion 1,200 Metastatic non-small cell lung cancer mg/20 mL (NSCLC) or urothelial carcinoma

* New active ingredient shown in bold type † The new active ingredient in Descovy is tenofovir alafenamide fumarate (TAF), which replaces tenofovir disoproxil fumarate (TDF) in the related product Truvada § Not available # Provisional consent The data sheets for currently marketed prescription medicines are published on the Medsafe website (www.medsafe.govt.nz/profs/Datasheet/dsform.asp).

28 Prescriber Update 2017; 38(2) June Mitochondrial Disorders: Medicines to Avoid Genetic mitochondrial diseases are due either to Key Messages mutations in the mitochondrial DNA (mtDNA) or the nuclear DNA (nDNA). Mitochondrial disease zz Medicines can affect a variety of can affect the brain, heart, liver, skeletal muscles, mitochondrial functions. kidney, endocrine system and respiratory zz Medicines that are toxic to mitochondrial systems. The symptoms within these systems are functions should be avoided in patients diverse and may be due to a number of different with mitochondrial disorders. defects within the mitochondria1,5. zz Due to the great diversity in mitochondrial Medicines can affect many of the different disease manifestations differing outcomes functions within the mitochondria. The can be reported in different patients for mitochondrial respiratory chain (MRC) is the same medicine. composed of five enzyme complexes: I-V and uses cytochrome c and coenzyme Q10, which act as Mitochondrial disorder (disease) is a collective electron carriers. Pharmacotherapy induced MRC term for a group of disorders that can affect many dysfunction may result from the direct inhibition different organs. There is no specific treatment of one or more of the enzyme complexes or for these disorders although the symptoms they uncoupling of oxidative phosphorylation. As the cause may be managed with medicines, surgery enzyme complexes are susceptible to free radical- or diet. One of the important aims of managing induced oxidative damage, medicines that cause patients with mitochondrial disorders is to oxidative stress may also result in MRC toxicity. avoid medicines that are toxic to mitochondrial The replication of mtDNA and protein synthesis functions1,2. may also be affected by medicines2,4. Mitochondria are thought originally to be free- High quality evidence of the effects of medicines living aerobic bacteria that were captured into in people with mitochondrial disease is sparse. non-bacterial cells. Mitochondria have their own Much of the available information is derived DNA that replicates independently of nuclear from in vitro or animal studies. Additionally, DNA under the control of enzymes similar to due to the great diversity in mitochondrial those in bacteria. Mitochondria are responsible disease manifestations, conflicting outcomes for energy production via the respiratory chain can be reported in different patients for the same and oxidative phosphorylation. Other functions medicine. Consensus appears to be lacking on include beta-oxidation, iron metabolism, copper which medicines should be completely avoided metabolism, heat production, apoptosis, calcium and which may be used with close monitoring1–5. signalling, haem synthesis, steroid synthesis and A summary of the available data is provided in amino acid metabolism2–4. Table 1.

Table 1: Medicines to avoid in patients with mitochondrial disease1–5*

Medicine Proposed mechanism Adverse effects related to mitochondrial toxicity Amiodarone Inhibits MRC I and III and beta Pulmonary toxicity, microvesicular oxidation steatosis and liver failure Antibiotics: Reduces mt protein synthesis Deafness, renal failure, myopathy gentamicin, chloramphenicol, tetracycline Anti-cancer medicines: mtDNA mutation Cardiomyopathy doxorubicin, cisplatin Antipsychotics: haloperidol, Inhibits MRC I, increases reactive Extrapyramidal symptoms, metabolic risperidone, clozapine oxygen species, inhibits oxidative syndrome phosphorylation Aspirin Inhibits oxidative phosphorylation Causes a Reye-like syndrome and beta oxidation

Prescriber Update 2017; 38(2) June 29 Beta-blockers: metoprolol, Inhibits MRC I Case report of muscle wasting propranolol Ciprofibrate Inhibits MRC I, weak peroxisome Myopathy and rhabdomyolysis proliferator activated receptor ligand Corticosteroids Inhibit mt membrane potential, Myopathy generate reactive oxygen species Fluoxetine Inhibits MRC I and V, interferes with Gastrointestinal damage cytochrome c Isoflurane Inhibits MRC I Hepatotoxicity Isoflurane / halothane / Inhibits MRC I Hepatotoxicity, neurotoxicity cardiac sevoflurane effects Linezolid Inhibits mt protein synthesis Polyneuropathy and lactic acidosis Local anaesthetics: Inhibtis MRC V, increases reactive Myopathy bupivicane, lidocaine oxygen species, inhibits oxidative phosphorylation Metformin Inhibits MRC I Causes lactic acidosis Nicotine Inhibits respiratory chain Non-steroidal anti- Inhibits oxidative phosphorylation Hepatotoxicity inflammatory drugs: and beta oxidation ibuprofen, diclofenac, naproxen Nucleoside reverse mtDNA depletion which then affects Encephalomyopathy, anaemia, transcriptase inhibitors: all functions polyneuropathy, pancreatitis and lactic zidovudine, didanosine, acidosis lamivudine, abacavir Paracetamol (overdose) MRC I Hepatotoxicity Phenytoin Inhibits mt ATPase Case report of intestinal pseudo obstruction, may cause hepatotoxicity Pioglitazone Inhibits MRC I, weak, peroxisome Increases anaerobic glycolysis proliferator activated receptor ligand Propofol (particularly > 4 mg/ Inhibition of free fatty acid entry to Propofol infusion syndrome: metabolic kg/h for > 48 hours) mt, beta oxidation acidosis, rhabdomyolysis, heart failure, hepatomegaly, asystole Sertraline Inhibits MRC I and V, inhibits Hepatotoxicity oxidative phosphorylation Simvastatin (other statins Inhibits MRC I, reduces coenzyme Causes myopathy, rhabdomyolysis have weaker effects) Q10 levels, weak peroxisome proliferator activated receptor ligand Sodium valproate Inhibits oxidative phosphorylation, Liver failure, hyperammoninaemia, beta-oxidation hypoglycaemia, steatosis and encephalopathy Tricyclic antidepressants: Inhibits MRC Extrapyramidal symptoms, memory amitriptyline, clomipramine impairment

* Table in alphabetical order, which is not the same as order of importance of the medicines. mt = mitochondria 3. Hargreaves IP, Al Sharhrani M, Wainwright L, et al. 2016. References Drug-induced mitochondrial toxicity. Drug Safety 39: 661–74. 1. Finsterer J, Segall L. 2010. Drugs interfering with 4. Nadanaciva S, Will Y. 2011. Investigating mitochondrial mitochondrial disorders. Drug and Chemical Toxicology dysfunction to increase drug safety in the pharmaceutical 33(2): 138–51. industry. Current Drug Targets 12: 774–82. 2. Moren C, Juarez-Flores DL, Cardellach F, et al. 2016. The role 5. Radboud Center for Mitochondrial Medicine. 2016. URL: of therapeutic drugs on acquired mitochondrial toxicity. www.rcmm.info/ (accessed 13 April 2017). Current drug metabolism 17: 648–62.

30 Prescriber Update 2017; 38(2) June Quarterly Summary of Recent Safety Communications The early warning system provides current and historical information on safety concerns for medicines and medical devices. These warnings are intended to help consumers and healthcare professionals make informed decisions about their use of medicines and medical devices. More information about the early warning system can be found on the Medsafe website (www. medsafe.govt.nz/Projects/B2/EWS.asp). Consumer information leaflets provide information about medicines and medical devices or medical conditions to consumers.

Date Communication Topic Animas Vibe Insulin Pump and Blood Glucose Analyser — Monitoring 24 March 2017 ongoing issues with screen fade, cracked battery casing and Communication other issues Alert 24 March 2017 Andrographis paniculata — potential risk for allergic reactions Communication

20 March 2017 Media release Primodos

Viekira Pak and Viekira Pak-RBV — Possible effects on Monitoring 13 March 2017 Communication blood glucose control when used in patients with type 2 diabetes Possible risk of hypothyroidism in infants exposed to iodine- Monitoring 2 March 2017 Communication containing contrast agents added to the medicines monitoring scheme Consumer Hydroxychloroquine — what you can expect when starting 2 March 2017 information leaflet treatment Consumer 8 February 2017 Medicines for Gout information leaflet If you would like to receive Medsafe’s early warning communications you can subscribe at www.medsafe.govt.nz/profs/subscribe.asp

WE NEED YOUR HELP! Please send your reports for these potential safety issues* listed in the table below.

Medicine Potential Safety Issue Active Monitoring Ends Viekira Pak, Viekira Pak-RBV Blood Glucose Control 31 December 2017 in Type 2 Diabetes

Iodinated Contrast Medium Hypothyroidism 30 September 2017 (Iodixanol, Iohexol, Ioversol, Iopamidol, Iodised oil, Diatrizoate sodium, Diatrizoate meglumine with sodium amidotrizoate)

• is a Medsafe scheme designed to collect more information on potential safety signals for specific medicines.

• Safety signals are identified from reports of adverse medicine reactions sent to the Centre for Adverse Reactions Monitoring (CARM). For further information see the Medsafe website.

• The scheme does not replace routine adverse reaction reporting. Find out how to report at: www.otago.ac.nz/carm or www.medsafe.govt.nz

Fax: (03) 479 7150 Phone: (03) 479 7247

Reporting form for Adverse Reactions to Medicines, Vaccines and Devices * The appearance of a possible safety issue in this scheme does not mean Medsafe and CARM have concluded that and all Clinical Events for IMMP PATIENT DETAILS HP3442 this medicine causes the reaction. Surname: First Name/s: NHI No:

Date of Birth: Sex:

Address:

Ethnicity:

ALL MEDICINES IN USE *ASTERISK SUSPECT MEDICINE/S* Include over-the-counter (OTC) and alternative medicines

Medicine or Vaccine+batch no. Daily Dose Route Date Started Date Stopped Reason for Use Prescriber Update 2017; 38(2) June (and brand name if known) 31

DESCRIPTION OF ADVERSE REACTION OR EVENT

Date of onset:

Recovered Not yet recovered but improved Not yet recovered Unknown Fatal - Date of Death:

Severe? - Yes No Rechallenged? - No Yes Result:

OTHER FACTORS - Please tick or specify as appropriate

Renal disease Allergy : Other Medical Conditions:

Hepatic disease Nutritional Suppl or OTC use : Industrial Chemicals :

REPORTER - Please tick as appropriate: Doctor Pharmacist Dentist Nurse Other :

Name: Address: Signature: Phone: Date:

Send completed form to CARM Freepost 112002, CARM, PO Box 913, Dunedin 9054 or Fax: (03) 479 7150 Subscribe to Printed Editions of Prescriber Update In response to the Prescriber Update survey in March 2016, Prescriber Update will gradually move towards a predominantly online publication. Print editions of Prescriber Update will continue to be supplied to organisations such as pharmacies and general practices, and will also be available to individuals who subscribe. If you would like to continue to receive a print edition of Prescriber Update, you must re-subscribe by emailing [email protected] with your name and postal address with the word ‘subscribe’ as the subject. Subscription to electronic copy of Prescriber Update can be found on the Medsafe website (www.medsafe.govt.nz/profs/subscribe.asp).

Medsafe Prescriber Update is published and New Zealand Medicines and Medical Devices distributed by Medsafe in the interests of Safety Authority safer, more effective use of medicines and A business unit of the Ministry of Health medical devices. Medsafe also acknowledges the contribution Editor of the New Zealand Pharmacovigilance Centre Dr Amanda Taylor in providing data and advice for articles. Medsafe, PO Box 5013, Wellington, New Zealand An electronic version of Prescriber Update is Ph: (04) 819 6800 available at www.medsafe.govt.nz/profs/ E-mail: [email protected] PUarticles.asp

Editorial Team To receive Prescriber Update electronically, Dr Geraldine Hill, Senior Medical Advisor please register at www.medsafe.govt.nz/ profs/subscribe.asp Jo Prankerd, Advisor Pharmacovigilance Lily Chan, Senior Advisor Data sheets, consumer medicine information, Pharmacovigilance media releases, medicine classification issues and adverse reaction forms can be found at Rowan Pollock, Manager, Clinical Risk www.medsafe.govt.nz Sue Scott, Principal Advisor, Medicines Control Published with the permission of the Director-General of Health. Dr Susan Kenyon, PhD, Principal Technical Specialist Dorothy Boyd, University of Otago This work is licensed under the Creative Acknowledgements Commons Attribution 4.0 Dr Alexander Bolotovski International licence. In Laurence Holding essence, you are free to: share, ie, copy and redistribute the material Dr Martin Bonne in any medium or format; adapt, ie, remix, Michael Haynes transform and build upon the material. You Riana Clarke must give appropriate credit, provide a link Dr Robin Whyman, Hawke’s Bay DHB to the licence and indicate if changes were made. Clinical Advisor Dr Geraldine Hill Group Manager Chris James

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32 Prescriber Update 2017; 38(2) June